Live-cell chemoproteomics yields a brain-penetrant covalent PIKfyve inhibitor with durable target occupancy
- Covalent hits from live-cell chemoproteomics were optimized for potency, selectivity and brain exposure using mass spectrometry, biochemical and in vivo assays.
- The compound, DUN'058, modifies a cysteine on a flexible loop away from the active site, showing chemoproteomics can reveal unexpected ligandable residues.
- Treatment activates TFEB-linked clearance pathways, and in mice target occupancy in brain persists well after the compound has cleared from circulation.
💡 Points Based on the abstract
A cysteine on a flexible loop away from the ATP site means selectivity likely comes from residue accessibility rather than hinge binding, a different game from reversible chemotypes like apilimod. Needed: a Cys-to-Ser mutant control and proteome-wide engagement at brain-relevant dose, plus resynthesis rate: durable occupancy makes chronic PIKfyve blockade (vacuolation) a real liability to test.
Chemoproteomics Discovery of a Central Nervous System-Penetrant Covalent Inhibitor of PIKfyve ↗